A 35-year-old on long-term phenytoin develops proximal muscle weakness, bone pain, and X-ray shows Looser's zones (Milkman's fractures) in the femoral necks bilaterally. Serum calcium is low, phosphate low, and ALP elevated. Which is the pathogenetic mechanism of this osteomalacia?

• A Phenytoin causes tubular phosphate wasting
• B Phenytoin blocks intestinal calcium absorption directly
• C Phenytoin reduces PTH secretion causing hypocalcemia
• D Phenytoin induces CYP450 enzymes increasing catabolism of 25-OH vitamin D ✓

Explanation

Phenytoin (and other anticonvulsants — carbamazepine, phenobarbitone) induces cytochrome P450 enzymes (CYP24A1) in the liver and intestine, increasing the hydroxylation and catabolism of 25-hydroxyvitamin D (calcidiol) into inactive metabolites. This results in vitamin D deficiency → osteomalacia with the classic features: low calcium, low phosphate, elevated ALP, Looser's zones (pseudofractures). The mechanism is accelerated vitamin D degradation, not tubular phosphate wasting (which causes X-linked hypophosphatemic rickets) or PTH suppression.

Reference: Maheshwari Essential Orthopaedics, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.